Pain can be a debilitating disorder that is difficult to treat. Much of the difficulty in treating pain may be associated with the varying physiological bases for different types of pain and may be due to the rather complex neurological basis for each type of pain. While complex, a great deal is known about pain transmission at the cellular and molecular level.
Referring to FIG. 1, a variety of neuronal cell types may be involved in the transmission or perception of pain. For example, Aβ, Aδ, and C primary afferent 10 fibers transmit signals from the periphery to the spinal cord 20. Cell bodies of the neurons with these fibers lie in dorsal root ganglion 30 and their axons pass through dorsal roots 40 prior to synapsing in the dorsal horn 50 of the spinal cord 20. More specifically, branches of these axons may ascend or descend a few vertebral segments in the tract of Lissauer, and axon collaterals may synapse with many neurons in the dorsal horn 50. These afferents 10 may synapse with inhibitory interneurons 500 or projection neurons 510 that send ascending projections through various ascending tracts 60 (see FIG. 2), such as the spinothalamic tract, the spinoreticular tract, the spinomesencephalic tract, or the spinocervical tract. The various ascending tracts 60 send projections to the thalamus or other midbrain structures.
For example, spinothalamic tract projection neurons may terminate in the medial nuclear group of the thalamus, including the central lateral nucleus and the ventral posterior lateral nucleus; spinoreticular tract projection neurons may terminate in the reticular formation of the pons or the thalamus; spinomesencephalic tract neurons may project to the mesencephalic reticular formation, the lateral part of the periaqueductal gray region, and other midbrain structures; and spinocervical tract neurons may project to midbrain nuclei and the thalamus, including the ventroposterior lateral and posterior medial nuclei. In these higher centers, in other regions of the brain receiving projections from these centers, or combinations thereof, pain may be perceived.
Descending fibers originating from, e.g., the periaqueductal gray matter, the nucleus raphe magnus or the nucleus paragigantocellularis, send projections in descending tracts 70 in the dorsolateral funiculus, directly or indirectly, to the dorsal horn 50 of the spinal cord 20, where they may synapse with interneurons or ascending projection neurons. The descending neurons that synapse with neurons in the dorsal horn 50 of the spinal cord are typically serotoninergic or noradrenergic neurons and may act to suppress activity of ascending projection neurons, especially those involved with nociception. Due in part to the large number of classes of neurons involved in pain transmission and perception, pain can be difficult to treat. In addition, pain may have different origins in different patients, making pain therapy management and strategy difficult. For example, some patients may benefit from inhibition of C fiber activity alone. Others may benefit from inhibition of Aβ fibers. Some may benefit from increased activity of Aα/Aβ fibers and descending neurons.
Further complicating the treatment of pain is the involvement of sympathetic neurons. Sympathetic neurons include projections in the spinal cord that originate from the brain to interneurons or to preganglionic neurons, interneurons, preganglionic neurons and postganglionic neurons. Sympathetic projections from the brain including brain stem, midbrain and forebrain to preganglionic sympathetic neurons or interneurons of the spinal cord include projections from brain areas such as the paraventricular nucleus of the hypothalamus, rostral ventrolateral medulla, ventromedial medulla, and caudal raphe nucleus. Preganglionic cell bodies of the sympathetic nerves and associated interneurons generally reside within the intermediolateral cell column of the lateral horn 80 of the spinal cord 20 at C1-S5. Generally, preganglionic sympathetic cell bodies send projections that exit the spinal cord through the ventral roots 90 to synapse with postganglionic neurons in sympathetic ganglia 100. Examples of sympathetic ganglia 100 include not only the chain of ganglia on each side of the spinal column, but also the inferior mesenteric, superior mesenteric, celiac, submandibular, otic, and pterygopalatine ganglia. Postganglionic nerves send projections that typically follow the vasculature to innervate end organs. Activity of sympathetic efferent fibers following peripheral nerve injury may cause burning pain, e.g., causalgia, or reflex sympathetic dystrophy syndrome. This activity is thought to cause pain by direct activation of damaged nociceptive afferent neurons or by nonsynaptic sympathetic transmission.
The sympathetic nervous system also comprises afferent fibers 140, which pass from the peripheral sympathetic system through the rami communicantes. Some of these fibers terminate about cell bodies within dorsal root ganglia 30. Cell bodies of some sympathetic afferents may be located in dorsal root ganglia 30 or sympathetic ganglia 100. Those ending in sympathetic ganglia 100 may send projections, direct or indirect to the lateral column 80 of the spinal cord 20. Shown in FIG. 1 are sympathetic afferent fibers, which project from discs 110 through sympathetic trunks via sympathetic ganglia 100 enter the spinal cord 20 through dorsal roots 40. Nerve endings in the vertebral discs are generally located in peripheral third of the disc.
Increased sympathetic activity has been implicated in increased pain in some circumstances and blocking of sympathetic neurons with drugs or electrical stimulation has been used to treat or prevent acute pain. In addition, RF and surgical lesions of the sympathetic chain are used to treat chronic pain. However, these are non-reversible therapies and may be difficult to repeat.
In addition to synapsing on inhibitory interneurons 500 and/or projection neurons 510, neurons of Aβ, Aδ, and C primary afferent fibers 10 may synapse on sympathetic efferent neurons 600 (see, e.g., FIG. 3). The connections between afferent inputs to the spinal cord and sympathetic efferent outputs may be an important target in the treatment of pain.
Spinal cord stimulation (SCS), while not perfect, has been useful for treating pain. The precise mechanism of action of SCS is not fully understood. As shown in FIG. 4, SCS typically involves stimulation via one or more epidurally placed electrode of a lead 120. FIG. 5 shows an alternative perspective view of a portion of a spinal cord 20 with epidural placement of a lead 120. In both FIG. 4 and FIG. 5, the lead 120 and its associated electrode(s) are positioned epidurally near the dorsal columns. A depolarizing electrical signal is delivered through the electrode(s). In theory, the depolarizing electrical signal excites ascending neurons 700 in the dorsal columns. The ascending neurons 700 in the dorsal column send collaterals that synapse with neurons in the dorsal horn 50, including primary afferents, inhibitory interneurons 500, and/or projection neurons 510. Stimulation of the dorsal column may to a lesser extent excite neurons in the descending tract 70, thereby enhancing the pain inhibiting effects of the descending transmissions. In addition, epidural SCS recruits large fibers, such as Aβ fibers, which can excite inhibitory interneurons 500 in the dorsal horn 50, thereby inhibiting transmission of pain signals through projection neurons 510 that run in ascending tracts 60. While lead 120 placement is in proximity to the dorsal columns, the effects of such electrical stimulation may spread to the dorsal roots 40 through the relatively conductive cerebrospinal fluid (CSF). Thus as described above, primary afferent Aβ fibers may be recruited and at least a portion of the treatment of pain may be due to effects on neurons in the dorsal roots 40. However, it is possible that the efficacy of such treatment is attenuated by effects at the dorsal roots 40 through stimulation of, e.g., C-fibers.
The efficacy of epidural electrical stimulation of the dorsal column can be quite high immediately after lead placement, e.g. approximately 60% for low back pain. However, within a few months the efficacy may drop as tolerance develops. For example, efficacy of dorsal SCS for treatment may drop to as little as 20% after about six months. The mechanisms for the development for such tolerance are not well understood. In addition to tolerance, epidural stimulation suffers from increased energy needs for the stimulation signal to cross the dura 130 and loss or inadvertent stimulation of dorsal roots due to CSF conductance.
Transcutaneous electrical neural stimulation (TENS) is another potential therapy for treatment of pain that has been shown to work well in rodent models. Many of such animal models involve artificially induced inflammation in a knee joint of a rat where TENS therapy is applied to the knee. Such models have shown that high frequency TENS is effective for treatment of primary and secondary hyperalgesia as well as morphine-tolerant secondary hyperalgesia, while low frequency TENS is effective for secondary hyperalgesia but not morphine-tolerant secondary algesia or primary hyperalgesia. In addition, much has been learned from such models about the mechanisms and interactions between peripheral pain and peripherally-applied TENS to central pain neurotransmission. For example, the effect of peripherally-applied TENS on central opioid, serotonin, muscarinic, and noradrenergic neurotransmission has become better understood. However, to date, TENS has not yet been shown to be consistently effective in treatment of pain, particularly low back pain. For low back pain, TENS may be impracticable as rather large leads and electrodes would likely be needed to provide a sufficient stimulation signal to deeper areas such as sympathetic ganglia 100 and dorsal roots 40. In addition, a TENS signal capable of stimulating such deeper structures in humans is also likely to stimulate unintended neurons causing side effects.
Accordingly, there remains a need for additional therapies to treat pain. Preferably such therapies increase efficacy over existing therapies or reduce tolerance relative to existing therapies.